A sensitive method for determination of the eight most prescribed drugs used in combined cardiovascular therapy in Serbia was developed and optimized. The method was based on SPE followed by LC/ion trap-MS/MS with positive electrospray ionization. Parameters that affect the SPE were optimized, such as the eluent, sample pH, and sample volume. Good recoveries from groundwater (87.6-120.9%) as well as wastewater (84.5-106.6%) were achieved with this method, except in the case of atorvastatin (26.1 and 45.2%, respectively). The method was applied in the analysis of four river water samples collected in Serbia, as well as nine corresponding groundwater samples. Residues of the P-blockers metoprolol and bisoprolol as well as the anticoagulant clopidogrel were detected for the first time in river water. Groundwater samples did not contain drug residues. Influents and effluents of two wastewater treatment plants showed the predominant presence of metoprolol and enalapril. The removal rate of metoprolol was generally low, whereas enalapril was eliminated with the highest efficiency. Atorvastatin was detected in influents and completely removed in the treatment.